Pharmaceutical products with HIV reverse transcriptase (including its resistant varieties) inhibitors are described in U.S. Pat. No. 5,519,021. An especially important compound among those disclosed is efavirenz, (4S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Efavirenz has the following structural formula:

This compound is used for the preparation of a medicament having nonnucleoside HIV-1 reverse transcriptase inhibiting activity that is useful in the prevention or treatment of infection by HIV and the treatment of AIDS. Efavirenz is sold commercially as SUSTIVA® by Bristol Myers Squibb.
WO patent application publication No. 98/33782 disclosed three crystalline forms, Form I (characterized by an x-ray powder diffraction patterns having peaks expressed as 2θ at 6.1, 6.4, 10.4, 10.9, 12.3, 13.2, 14.2, 15.2, 16.9, 18.4, 19.2, 20.1, 21.2, 22.3, 23.0, 24.9, 25.9, 26.3, 27.2, 28.1, 28.6, 29.1, 29.5, 30.7, 32.4 and 38.3 degrees), Form II (characterized by an x-ray powder diffraction patterns having peaks expressed as 2θ at 3.6, 6.3, 11.1, 12.8, 13.3, 14.3, 16.1, 16.9, 18.5, 19.2, 19.6, 20.6, 21.3, 22.6, 23.2, 24.4, 24.9, 26.0, 26.8, 27.6, 28.4, 29.2, 29.6, 30.6, 31.9 and 33.8 degrees) and Form III (characterized by an x-ray powder diffraction patterns having peaks expressed as 2θ at 7.2, 10.9, 13.7, 14.5, 16.7, 19.1, 19.6, 20.8, 21.7, 22.3, 22.8, 23.2, 23.9, 24.5, 24.9, 25.8, 27.0, 27.6, 29.3, 30.3, 30.7, 31.3, 33.4, 38.4 and 39.2 degrees) of efavirenz.
WO patent application publication No. 99/64405 disclosed five crystalline forms, Form 1 (characterized by an x-ray powder diffraction patterns having peaks expressed as 2θ at about 6.0, 6.3, 10.3, 10.8, 14.1, 16.8, 20.0, 20.5, 21.1 and 24.8 degrees), Form 2 (characterized by an x-ray powder diffraction patterns having peaks expressed as 2θ at about 6.8, 9.2, 12.3, 16.2, 21.4, 22.7, 24.1 and 28.0 degrees), Form 3 (characterized by an x-ray powder diffraction patterns having peaks expressed as 2θ at about 7.1, 7.3, 11.0, 13.8, 20.9, 23.3, 27.9 and 33.5 degrees), Form 4 (characterized by an x-ray powder diffraction patterns having peaks expressed as 2θ at about 3.6, 6.3, 9.7, 11.0, 12.7, 13.2, 16.1, 19.2, 19.5, 20.6 and 24.3 degrees) and Form 5 (characterized by an x-ray powder diffraction patterns having peaks expressed as 2θ at about 10.2, 11.4, 11.6, 12.6, 19.1, 20.6, 21.3, 22.8, 24.8, 27.4, 28.2 and 31.6 degrees) of efavirenz.
WO patent application publication No. 2006/018853 disclosed crystalline form H1 and amorphous of efavirenz.
WO patent application publication No. 2006/040643 disclosed the crystalline forms of efavirenz form alpha, form beta, form gamma, form gamma1, form gamma2, form omega, form delta, form N, form O and form P.
WO patent application publication No. WO2008/108630 disclosed the crystalline forms of efavirenz form ULT-1 and form ULT-2.
The known crystalline form H1 disclosed in WO 2006/018853, has been found to be hygroscopic on longer duration of storage. Thus, for example, water content of crystalline form H1 disclosed in WO 2006/018853 is increased by 2.37% in six months studied at the temperature of 25° C. under relative humidity of 60%.
We have found that, when crystalline form H1 is prepared under controlled conditions, the product obtained is non-hygroscopic. The non-hygroscopic nature of form H1 obtained by the process of the present invention is exhibited by the fact that there is no substantial change in the water content even in longer duration of storage and during the pharmaceutical preparations. Thus, for example, water content of crystalline form H1 produced according to the present invention is increased by 0.2% in six months at the temperature of 25° C. under relative humidity of 60%.
According to object of the present invention, therefore, is to provide a process for preparing non-hygroscopic crystalline form H1 of efavirenz, and pharmaceutical preparations comprising non-hygroscopic crystalline form H1 of efavirenz.